Influence of Nonspecific Interactions between Proteins and In Vivo Cytoplasmic Crowders in Facilitated Diffusion of Proteins: Theoretical Insights

Abstract

The binding of proteins to their respective specific sites on the DNA through facilitated diffusion serves as the initial step of various important biological processes. While this search process has been thoroughly investigated viain vitro studies, the cellular environment is complex and may interfere with the protein’s search dynamics. The cytosol is heavily crowded, which can potentially modify the search by nonspecifically interacting with the protein that has been mostly overlooked. In this work, we probe the target search dynamics in the presence of explicit crowding agents that have an affinity toward the protein. We theoretically investigate the role of such protein–crowder associations in the target search process using a discrete-state stochastic framework that allows for the analytical description of dynamic properties. It is found that stronger nonspecific associations between the crowder and proteins can accelerate the facilitated diffusion of proteins in comparison with a purely inert, rather weakly interacting cellular environment. This effect depends on how strong these associations are, the spatial positions of the target with respect to the crowders, and the size of the crowded region. Our theoretical results are also tested with Monte Carlo computer simulations. Our predictions are in qualitative agreement with existing experimental observations and computational studies.